Changes in the blood vessels of the brain have been linked to Alzheimer’s disease (AD), and deterioration of the blood-brain barrier may be an early sign of the disease. But how the brain’s vasculature changes on the molecular level has remained largely unknown, hindering the development of therapies. A study profiling gene expression of the brain’s blood vessels revealed AD changes in unprecedented detail. The results provide a map to guide potential future therapies targeting blood-brain barrier dysfunction in Alzheimer’s.

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Despite its relatively small size, the adult brain accounts for about one-fifth of the body’s energy usage. To meet the high energy needs, the brain is supported by an extensive network of blood vessels with a staggering equivalent of about 400 miles of capillaries. The combination of the brain’s vulnerability to change in the microenvironment and its high nutrient demand led to the evolution of the blood-brain barrier (BBB), which lines the walls of the brain’s capillaries.

The BBB is a semipermeable protective border between the blood in the brain’s vascular system and the brain’s tissue. It strictly controls the particles that can enter the brain from the bloodstream, and also provides pathways for clearance of amyloid beta and other debris. Loss of its integrity allows the entrance of toxic molecules, pathogens and cells from the blood into the brain that may trigger inflammatory and immune responses. The breakdown of the BBB also has been shown to occur in patients with AD. However, the full impact of changes to the barrier in the course of the disease has remained elusive.

Unlike prior investigations of the brain’s vasculature, this study was instrumental in profiling intact blood vessels. The research examined six brain regions from autopsy tissue of 220 AD patients and 208 age-matched controls. Most samples were from people ranging in age from early 80s to 90s, with AD cases from early- to late-stage disease.

The blood-brain barrier is made of multiple cell types. The study isolated more than 22,000 cells which, based on their patterns of gene expression, were grouped into 11 cellular subtypes. These included cell types critical for the support of the BBB, such as endothelial cells that line the brain’s capillaries and control the passage of molecules through the BBB; pericytes that wrap around endothelial cells and provide structural and functional support; smooth muscle cells that regulate blood flow and pressure; and fibroblasts that stabilize blood vessels.

The research found large differences in how genes were turned on and off across the diverse cell types of the BBB throughout the different regions of the brain that were examined. The findings suggest that the BBB is not uniform throughout the brain, and that in some regions, the BBB may be more vulnerable to damage.

In people with AD, the research identified nearly 2,700 genes that were turned on or off differently than those in the control group. Included were genes that maintained the blood-brain barrier’s integrity, genes linked to inflammation and genes for the transportation of molecules across the BBB, suggesting that important transport and barrier properties are altered in Alzheimer’s. Interestingly, in AD there was lower expression of the transporter gene ABCB1, which codes for a type of protein pump that helps clear amyloid beta from the brain and seems to work less efficiently in people with AD.

The changes in gene expression also suggest that signaling between vascular cells and brain cells could be affected and may explain some aspects of BBB dysfunction in Alzheimer’s. Cells are constantly passing signals to each other, coordinating biological processes and responding to changes. When signaling breaks down, their ability to function properly becomes impaired. The study found that among the altered signaling pathways were those needed to build the extracellular matrix, a network of proteins and other molecules outside of cells that provides for their structural support. This further adds to the body of evidence that the BBB’s integrity may be compromised in AD, impairing its proper function.

Out of the 2,700 dysregulated genes in AD found in this study, 125 could be linked to previously identified AD-associated genetic variants. Some of the changes in gene activity were more common in people who carried the APOE4 allele, which is the strongest genetic risk factor for sporadic Alzheimer’s. This suggests that the activity of genes in the vasculature of APOE4 carriers is distinct from that in AD, and that changes to the blood vessels in APOE4 carriers may be key to the increased risk for the disease.

In summary, the research contributes to our increased understanding of the gene expression changes that may be negatively impacting the blood-brain barrier’s integrity in Alzheimer’s. As breakdown of the BBB may occur early in AD, even before neurodegeneration and memory decline, the study provides valuable insights into novel molecular signaling pathways that may go awry in the brain’s vasculature that could be targeted by future therapies directed at the BBB in the early stages of disease.

Published in Nature Neuroscience:

Single-nucleus multi-region transcriptomic analysis of brain vasculature in Alzheimer’s Disease

Li-Huei Tsai, Ph.D., Massachusetts Institute of Technology; Broad Institute

Manolis Kellis, Ph.D., Massachusetts Institute of Technology; Broad Institute